Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin-immunoreactive dystrophic neurites in the CA2/3 region of the hippocampus are characteristic of diffuse Lewy body disease (DLBD). The origin of dystrophic CA2/3 neurites is unknown, but their extent correlates with the number of cortical Lewy bodies (LBs). To examine the molecular composition of these lesions, hippocampal sections were obtained at postmortem from cases of DLBD, Parkinson's disease and Alzheimer's disease. The tissue samples were fixed in a variety of fixatives and immunostained with antibodies to ubiquitin, ubiquitin C-terminal hydrolase (PGP9.5), neurofilament protein subunits, tau protein, paired helical filaments and tyrosine hydroxylase (TH). In addition to being ubiquitin positive, both cortical LBs and CA2/3 dystrophic neurites were positive with a neurofilament monoclonal antibody (RM032) and PGP9.5; however, fewer lesions were detected with these antibodies compared to ubiquitin immunocytochemistry. The dystrophic CA2/3 neurites were not stained with antibodies to tau proteins, paired helical filaments or TH. Absence of TH immunoreactivity suggests that CA2/3 neuritic processes are not derived from brain stem dopaminergic afferents to the hippocampus. Since CA2/3 neurites are immunologically similar to cortical LB, the pathogenesis of these lesions may be similar. Characterization of dystrophic CA2/3 neurites and cortical LBs may clarify how these lesions contribute to the emergence of dementia in DLBD.
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PMID:Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. 791 27

A genetic contribution to the etiology of Parkinson's disease was first suspected by Charcot and later confirmed by case control, family, and twin studies, as well as by the description of large parkinsonian families with Mendelian inheritance of the disease. Recent progress in the field of molecular neurogenetics has led to the identification of several Parkinson disease genes and gene loci. Mutations in the alpha-Synuclein gene (PARK1) and in the gene for the ubiquitin C-terminal hydrolase I (PARK5), along with two gene loci harboring currently unknown genes (PARK3 and PARK4), have been linked to very rare autosomal dominantly inherited parkinsonian syndromes. Mutations in the parkins gene (PARK2), causing autosomal recessive early-onset parkinsonism, are much more common and therefore of clinical relevance. A second gene locus for an autosomal dominantly inherited Parkinsonian syndrome was recently localized on chromosome 1 (PARK6). All three parkinson genes identified thus far imply the involvement of the ubiquitin pathway of protein degradation in the pathogenesis of Parkinson's disease.
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PMID:[The genetics of Parkinson syndrome]. 1144 21

Recent studies suggest that ubiquitin C-terminal hydrolase-L1 (UCH-L1), a neuronal deubiquitinating enzyme, represents a candidate gene responsible for either the development of familial Parkinson's disease (PD) or the protection against sporadic PD in Caucasian populations, although these findings are not fully verified in non-Caucasian populations. To determine an association of the variations in the UCH-L1 gene with development of sporadic PD in a Japanese population, a Ser18Tyr polymorphism and an Ile93Met mutation were studied by PCR-RFLP analysis in 74 Japanese patients with sporadic PD and 155 age-matched non-PD controls. The frequency of 18Tyr allele was significantly lower in PD patients than the controls (38.5% vs. 53.5%) (chi(2)=9.064, p=0.0026; the odds ratio=1.84, 95% confident interval=1.23-2.74). Furthermore, the frequency of 18Tyr/Tyr homozygotes was significantly lower in PD patients than the controls (14.9% vs. 33.5%), compared with that of two other genotypes combined (chi(2)=8.767, p=0.0031; the odds ratio=0.35, 95% confident interval=0.27-0.45). The Ile93Met substitution was not detected in any Japanese subjects examined. These results indicate that the presence of 18Tyr allele and 18Tyr/Tyr homozygosity in the UCH-L1 gene is associated with a reduced risk for development of sporadic PD in a Japanese population, supporting the previous observations on sporadic PD in Caucasian populations.
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PMID:A polymorphic variation of serine to tyrosine at codon 18 in the ubiquitin C-terminal hydrolase-L1 gene is associated with a reduced risk of sporadic Parkinson's disease in a Japanese population. 1153 41

Over the past few years, several genes for monogenically inherited forms of Parkinson's disease (PD) have been mapped and/or cloned. In a small number of families with autosomal dominant inheritance and typical Lewy-body pathology, mutations have been identified in the gene for alpha-synuclein. Aggregation of this protein in Lewy-bodies may be a crucial step in the molecular pathogenesis of familial and sporadic PD. On the other hand, mutations in the parkin gene cause autosomal recessive parkinsonism of early onset. In this form of PD, nigral degeneration is not accompanied by Lewy-body formation. Parkin-mutations appear to be a common cause of PD in patients with very early onset. Parkin has been implicated in the cellular protein degradation pathways, as it has been shown that it functions as a ubiquitin ligase. The potential importance of this pathway is also highlighted by the finding of a mutation in the gene for ubiquitin C-terminal hydrolase L1 in another small family with PD. Other loci have been mapped to chromosome 2p and 4p, respectively, in a small number of families with dominantly inherited PD, but those genes have not yet been identified. These findings prove that there are several genetically distinct forms of PD that can be caused by mutations in single genes. On the other hand, there is at present no direct evidence that any of these genes have a direct role in the aetiology of the common sporadic form of PD. Epidemiological, case control, and twin studies, although supporting a genetic contribution to the development of PD, all suggest a clear familial clustering only in a minority of cases. It is therefore widely believed that a combination of interacting genetic and environmental causes may be responsible in this majority of PD-cases. However, studies of gene-environment interactions have not yet produced any convincing results. Nevertheless, the elucidation of the molecular sequence of events leading to nigral degeneration in clearly inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.
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PMID:Genetics of Parkinson's disease. 1169 18

Mutations in alpha-synuclein, parkin and ubiquitin C-terminal hydrolase L1, and defects in 26/20S proteasomes, cause or are associated with the development of familial and sporadic Parkinson's disease (PD). This suggests that failure of the ubiquitin-proteasome system (UPS) to degrade abnormal proteins may underlie nigral degeneration and Lewy body formation that occur in PD. To explore this concept, we studied the effects of lactacystin-mediated inhibition of 26/20S proteasomal function and ubiquitin aldehyde (UbA)-induced impairment of ubiquitin C-terminal hydrolase (UCH) activity in fetal rat ventral mesencephalic cultures. We demonstrate that both lactacystin and UbA caused concentration-dependent and preferential degeneration of dopaminergic neurons. Inhibition of 26/20S proteasomal function was accompanied by the accumulation of alpha-synuclein and ubiquitin, and the formation of inclusions that were immunoreactive for these proteins, in the cytoplasm of VM neurons. Inhibition of UCH was associated with a loss of ubiquitin immunoreactivity in the cytoplasm of VM neurons, but there was a marked and localized increase in alpha-synuclein staining which may represent the formation of inclusions bodies in VM neurons. These findings provide direct evidence that impaired protein clearance can induce dopaminergic cell death and the formation of proteinaceous inclusion bodies in VM neurons. This study supports the concept that defects in the UPS may underlie nigral pathology in familial and sporadic forms of PD.
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PMID:Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. 1206 77

Although originally discounted, hereditary factors have emerged as the focus of research in Parkinson's disease (PD). Genetic studies have identified mutations in alpha-synuclein and ubiquitin C-terminal hydrolase as rare causes of autosomal dominant PD and mutations in parkin as a cause of autosomal recessive PD. Functional characterization of the identified disease genes implicates the ubiquitin-mediated protein degradation pathway in these hereditary forms of PD and also in the more common sporadic forms of PD. Subsequent identification of further loci in familial PD and diverse genetic factors modulating the risk for sporadic PD point to substantial genetic heterogeneity in the disease. Thus, new candidate genes are expected to encode proteins either involved in ubiquitin-mediated protein degradation or sequestrated in intracytoplasmic protein aggregations. Future identification of disease genes is required to confirm this hypothesis, thereby unifying the clinical and genetic heterogeneity of PD, including the common sporadic form of the disease, by one biochemical pathway.
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PMID:Parkinson's disease: one biochemical pathway to fit all genes? 1206 34

Many studies have suggested the ubiquitin-proteasome system played an essential role in the pathogenesis of neurodegenerative disorders. In 1999, we provided evidence that a mutation of the system could directly cause neurodegeneration using the gad mouse. Namely, we identified the gad mutation was caused by an intragenic deletion of a gene encoding ubiquitin C-terminal hydrolase 1(UCH-L1), which is a member of de-ubiquitinating enzyme family. In human, missense mutation of UCH-L1 gene was reported in a German family with Parkinson's disease. As well, the parkin gene product was revealed to be an E3 ubiquitin ligase which recognize a form of alpha-synuclein as a substrate. Thus, the investigation of the ubiquitin-proteasome system should provide a clue for understanding neurodegeneration. We have characterized UCH-L1 and identified candidates of endogenous substrates as well as interacting proteins of UCH-L1. In addition, we found amount of monomeric ubiquitin was decreased in the brain of the gad mouse compared with wild type mice. We have also tried to develop "protein therapy" using UCH-L1 protein with TAT sequence. We observed the protein was delivered to brain after intraperitoneal injection in the wild type mouse. This approach would provide a new therapeutic strategy for neurodegeneration.
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PMID:[The ubiquitin-proteasome system and neurodegeneration]. 1223 99

The assumption that each enzyme expresses a single enzymatic activity in vivo is challenged by the linkage of the neuronal enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1) to Parkinson's disease (PD). UCH-L1, especially those variants linked to higher susceptibility to PD, causes the accumulation of alpha-synuclein in cultured cells, an effect that cannot be explained by its recognized hydrolase activity. UCH-L1 is shown here to exhibit a second, dimerization-dependent, ubiquityl ligase activity. A polymorphic variant of UCH-L1 that is associated with decreased PD risk (S18Y) has reduced ligase activity but comparable hydrolase activity as the wild-type enzyme. Thus, the ligase activity as well as the hydrolase activity of UCH-L1 may play a role in proteasomal protein degradation, a critical process for neuronal health.
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PMID:The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. 1240 65

Parkinson's disease (PD) is characterized pathologically by preferential degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). Nigral cell death is accompanied by the accumulation of a wide range of poorly degraded proteins and the formation of proteinaceous inclusions (Lewy bodies) in dopaminergic neurons. Mutations in the genes encoding alpha-synuclein and two enzymes of the ubiquitin-proteasome system, parkin and ubiquitin C-terminal hydrolase L1, are associated with neurodegeneration in some familial forms of PD. We now show that, in comparison to age-matched controls, alpha-subunits (but not beta-subunits) of 26/20S proteasomes are lost within dopaminergic neurons and 20S proteasomal enzymatic activities are impaired in the SNc in sporadic PD. In addition, while the levels of the PA700 proteasome activator are reduced in the SNc in PD, PA700 expression is increased in other brain regions such as the frontal cortex and striatum. We also found that levels of the PA28 proteasome activator are very low to almost undetectable in the SNc compared to other brain areas in both normal and PD subjects. These findings suggest that failure of the ubiquitin-proteasome system to adequately clear unwanted proteins may underlie vulnerability and degeneration of the SNc in both sporadic and familial PD.
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PMID:Altered proteasomal function in sporadic Parkinson's disease. 1250 66

The etiopathogenesis of Parkinson's disease (PD) has been elusive. Recently, several lines of evidence have converged to suggest that defects in the ubiquitin-proteasome system and proteolytic stress underlie nigral pathology in both familial and sporadic forms of the illness. In support of this concept, mutations in alpha-synuclein that cause the protein to misfold and resist proteasomal degradation cause familial PD. Similarly, mutations in two enzymes involved in the normal function of the ubiquitin-proteasome system, parkin and ubiquitin C-terminal hydrolase L1, are also associated with hereditary PD. Furthermore, structural and function defects in 26/20S proteasomes with accumulation and aggregation of potentially cytotoxic abnormal proteins have been identified in the substantia nigra pars compacta of patients with sporadic PD. Thus, a defect in protein handling appears to be a common factor in sporadic and the various familial forms of PD. This hypothesis may also account for the vulnerability of the substantia nigra pars compacta in PD, why the disorder is age related, and the nature of the Lewy body. It has also facilitated the development of experimental models that recapitulate the behavioral and pathological features of PD, and hopefully will lead to the development of novel neuroprotective therapies for the disorder.
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PMID:Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson's disease. 1266


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